Rotigotine is the International Non-Proprietary Name (INN) of the compound (−)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]-amino]-1-naphthalenol, having the structure shown below

Rotigotine is a non-ergolinic D1/D2/D3 dopamine agonist that resembles dopamine structurally and has a similar receptor profile but a higher receptor affinity.
In contrast to other non-ergolinic dopamine agonists, rotigotine has significant D1 activity, which may contribute to a more physiological action.
In contrast to ergolinic compounds, rotigotine has a very low affinity for 5 HT2B receptors and thus a low risk of inducing fibrosis. Actions on non-dopaminergic receptors (such as 5-HT1A agonism and A2B antagonism) may contribute to other beneficial effects, such as antidyskinetic activity, neuroprotective activity and antidepressive effects.
Rotigotine is disclosed as active agent for treating patients suffering from Parkinson's disease (WO 2002/089777), Parkinson's plus syndrome (WO 2005/092331), depression (WO 2005/009424) and the restless-legs syndrome (WO 2003/092677) as well as for the treatment or prevention of dopaminergic neurone loss (WO 2005/063237).
Rotigotine has been tested in the form of its free base or as rotigotine hydrochloride.
The Restless Leg Syndrome (RLS) is a neurological disease that expresses itself as a false sensation in the legs accompanied by a strong kinetic urge. Symptoms of RLS include tingling, pulling, aching, itching, burning, cramps or pain, causing in the person concerned the irresistible urge to move. This disorder occurs most frequently when the person concerned is resting. Therapy studies have revealed a diversity of results obtained in monotherapeutic treatments with dopamine agonists, opiates, benzodiazepines, carbamazepine, clonidine or levodopa (L-DOPA) in combination with a dopa decarboxylase inhibitor. The use of L-DOPA for treating RLS has been the subject of a particularly large number of papers. Long-term L-DOPA therapy leads to a clear mitigation of the disorder with an improved quality of sleep and life. The drawback of most conventional monotherapies is that, depending on the duration of the therapy, the amount of the active ingredient must be progressively increased in order to ensure the success of the treatment. A surprising discovery has shown that the monotherapeutic administration of a rotigotine-containing transepicutaneous composition especially when in the form of a patch composition leads to the suppression and reduction of the RLS symptoms, with rotigotine as the active substance. Parkinson's disease is believed to be primarily caused by the degeneration of dopaminergic neurons in the substantia nigra. Parkinson's disease is primarily a disease of middle age and beyond, and it affects both men and women equally. The highest rate of occurrence of Parkinson's disease is in the age group over 70 years old, where Parkinson's disease exists in 1.5 to 2.5% of that population. The mean age at onset is between 58 and 62 years of age, and most patients develop Parkinson's disease between the ages of 50 and 79. There are approximately 800,000 people in the United States with Parkinson's disease. The clinical diagnosis of Parkinson's disease is based on the presence of characteristic physical signs. The disease is known to be gradual in onset, slowly progressive, and variable in clinical manifestation. Evidence suggests that the striatal dopamine content declines to 20% below levels found in age-matched controls before symptoms occur.
Treatment of Parkinson's disease has been attempted with, inter alia, L-dopa (levodopa), which still is the gold standard for the therapy of Parkinson's disease. Levodopa passes the blood-brain barrier as a precursor for dopamine and is then converted into dopamine in the brain. L-dopa improves the symptoms of Parkinson's disease but may cause severe side effects. Moreover, the drug tends to lose its effectiveness after the first two to three years of treatment. After five to six years, only 25% to 50% of patients maintain improvement. Furthermore a major drawback of currently utilized therapies for Parkinson's disease is the eventual manifestation of the “fluctuation syndrome”, resulting in “all-or-none” conditions characterized by alternating “on” periods of mobility with dyskinesias and “off” periods with hypokinesia or akinesia.
Patients who display unpredictable or erratic “on-off” phenomena with oral anti-Parkinson therapy have a predictable beneficial response to i.v. administration of L-dopa and other dopamine agonists, suggesting that fluctuations in plasma concentrations of drug are responsible for the “on-off” phenomena. The frequency of “on-off” fluctuations has also been improved by continuous infusions of the dopamine receptor agonists apomorphine and lisuride. However, this mode of administration is inconvenient. Therefore, other modes of administration providing a more constant plasma level, such as topical administration, are beneficial and have been suggested in the past.
Transdermal drug delivery is an alternative for oral drug delivery and hypodermic injections. Different delivery methods have been investigated over the years to increase the drug delivery through the skin. Transdermal delivery is a well-established method of drug administration whereby the hepatic first-pass effect is circumvented. Several studies into the transdermal delivery of rotigotine have been carried out. The results showed a significant increase in bioavailability in comparison to oral delivery and providing a continuous delivery pattern. Monotherapy of rotigotine via passive diffusion controlled transdermal application is however limited by the skin permeability and may require dose titration to meet individual therapeutic needs. To date, various transdermal therapeutic systems (US) for the administration of rotigotine have been described.
WO 94/07468 discloses a transdermal therapeutic system containing rotigotine hydrochloride as active substance in a two-phase matrix which is essentially formed by a hydrophobic polymer material as a continuous phase and a disperse hydrophilic phase contained therein and mainly containing the drug and hydrated silica. The silica enhances the maximum possible loading of the US with the hydrophilic salt.
Moreover, the formulation of WO 94/07468 usually contains additional hydrophobic solvents, permeation-promoting substances, dispersing agents and, in particular, an emulsifier which is required to emulsify the aqueous solution of the active principle in the lipophilic polymer phase. A TTS, prepared by using such a system, has been tested in healthy subjects and Parkinson patients. The average drug plasma levels obtained by using this system were around 0.15 ng/mL with a 20 cm2 patch containing 10 mg rotigotine hydrochloride. This level is considered too low to achieve a truly efficacious treatment or alleviation of the symptoms related to Parkinson's Disease.
Various further transdermal therapeutic systems (US) have been described for example in WO 99/49852. The US comprises a backing layer, inert with respect to the constituents of the matrix, a self-adhesive matrix layer containing an effective quantity of rotigotine or rotigotine hydrochloride and a protective film which is to be removed before use. The matrix system is composed of a non-aqueous polymer adhesive system, based on acrylate or silicone.
In the transdermal delivery system (TDS, which is used synonymous for US) according to W094/07468 and many related applications, the drug crosses the membrane by passive diffusion. A disadvantage of these types of transdermal administration is that there is very limited dosing flexibility available, e.g. in view of individual dosing, limited maximum daily dose, on demand application, continuous or pulsatile administration pattern, period of administration.
However, as the skin is to be seen as a very efficient barrier for most drug candidates, such type of membrane controlled systems are more or less limited in practice to transdermal delivery of active substances that reveal a very high skin permeability. Additionally, special requirements on drug release kinetics have to be met like contact delivery over several days. The rotigotine flux obtained with these passive transdermal therapeutic systems is not necessarily sufficient for all patients.
Different delivery methods have been investigated over the years to increase the drug delivery through the skin.
There have been several attempts to increase the rates of transdermal drug delivery by using of alternative energy sources such as electrical energy and ultrasonic energy. Electrically assisted transdermal delivery is also referred to as electro transport. The term “electro transport” or “electromotive administration” as used herein refers generally to the delivery of an agent (e.g. a drug) through a membrane, such as skin, mucous membrane, or nails. One of the possibilities is iontophoresis. By applying a small current across the skin it is possible to enhance the transdermal delivery of small charged ionic molecules. Iontophoresis involves the application of an electromotive force to drive or repel ions through the dermal layers into a target tissue. Particularly suitable target tissues include those adjacent to the delivery site for localized treatment. Uncharged molecules can also be delivered using iontophoresis via a process called electroosmosis. This technology of “electro transport” offers several advantages over e.g. oral and injection or passive transdermal drug delivery. Key advantages of ionthophoretic drug delivery include the avoidance of pain and potential for infection associated with needle injection, the ability to control the rate of drug delivery, the ability to programme the drug-delivery profile and the minimisation of local tissue trauma.
One of the interesting properties of this technique is the possibility to modulate the transport rate into and through the skin. This is an important advantage for drugs with a narrow therapeutic window, such as dopamine agonists.
Iontophoretic transdermal delivery relates to introducing ions or soluble salts of pharmaceutically active compounds into tissues of the body under the influence of an applied electric field.
In certain cases, e.g., when transdermal delivery by means of passive diffusion controlled patches appears to be ineffective or unacceptable because of low passage through the skin, leading to very large patches, iontophoretic transdermal delivery may provide an advantageous method of delivering that compound. Further iontophoretic transdermal delivery has the major advantage that the administered amount can be regulated precisely and can be used to easily titrate patients up to a certain level of administration over a period of up to several weeks.
Electrotransport devices use at least two electrodes that are in electric contact with some portion of the skin, nails, mucous membrane, or other surface of the body. One electrode, commonly called the “donor” electrode, is the electrode from which the agent is delivered into the body. The other electrode, typically termed the “counter” electrode, serves to close the electrical circuit through the body. For example, if the agent to be delivered is positively charged, i.e., a cation, then the anode is the donor electrode, while the cathode is the counter electrode which serves to complete the circuit. Alternatively, if an agent is negatively charged, i.e., an anion, the cathode is the donor electrode and the anode is the counter electrode. Additionally, both the anode and cathode may be considered donor electrodes if both anionic and cationic agent ions, or if uncharged dissolved agents, are to be delivered. Furthermore, electrotransport delivery systems generally require at least one (drug) reservoir or source of the agent to be delivered to the body.
Iontophoresis is well established for use in transdermal drug delivery. The advantage of this method is that unlike transdermal patches, it relies on active transportation within an electric field. It allows the delivery of water-soluble ionic drugs that are not effectively absorbed through the skin. In the presence of an electric field electromigration and electroosmosis are the dominant forces in mass transport. These movements are measured in units of chemical flux, commonly μmol/cm2 h. There are a number of factors that influence iontophoretic transport including skin pH, drug concentration and characteristics, ionic competition, molecular size, current, voltage, time applied and skin resistance.
The advantage of this technique (e.g. iontophoresis) is that the flux can be accurately controlled and manipulated by the externally applied current. The level of enhancement that can be achieved is, for a large part, dependent on the charge, the lipophilicity, and the molecular weight of the drug. Compounds that enhance the percutaneous penetration of a drug have been applied widely in passive transdermal studies, although the applicability of these compounds in humans is limited by the level of skin irritation that they may evoke. lontophoresis is a technique that allows movement of ions of soluble salts across a membrane under an externally applied potential difference that is induced across the skin by a low-voltage electric current. The application of current is controlled by an electronic device that adjusts the voltage in response to the changes in skin electrical resistance. Charged drug as well as other ions are carried across the skin as a component of induced ion flow. Numerous factors affect iontophoretic delivery, including flux proportionality with respect to applied current density and the presence of ions other than drug. Current up to 0.5 mA/cm2 is believed to be tolerable for patients. The onset of action with iontophoretic treatment is rapid, in contrast to hours for passive transdermal delivery. Since drug delivery is proportional to applied current, significant advantages of iontophoresis include the possibility of preprogramming the drug delivery, dose tailoring on an individual basis, or time tailoring in a constant or pulsatile fashion.
Compared to passive transdermal delivery, iontophoresis provides for several advantages which are useful in the treatment of Parkinson's disease: it allows programming of the flux at the required therapeutic rate by adjusting the electric current. It is advantageous for a patient in need of a drug that the drug amount can be adjusted to the individual need. Another advantage is that iontophoresis allows for continuous as well as pulsatile administration and it permits a rapid start or termination of administration of the medication, if needed, by simply turning the iontophoretic delivery system on or off.
It is advantageous that control of the rate and duration of drug delivery can be handled in a way to avoid the potential risk of overdose and the discomfort of an insufficient dosage.
However, in any given electro transport process, more than one process, including at least some “passive” diffusion, may be occurring simultaneously to a certain extent. Accordingly, the term “electro transport” or “electromotive administration”, as used herein, should be given its broadest possible interpretation so that it includes the electrically induced or enhanced transport of at least one agent, which may be charged, uncharged, or a mixture thereof, whatever the specific mechanism or mechanisms by which the agent actually is transported. For example the total iontophoretic flux consists of the passive flux (Jpass), the electro-osmotic flux (JEO) and the electromigrative flux (JEM). The latter two are representing the iontophotetic flux.
Another dopamine agonist which has been used in the treatment of Parkinson's disease is R-apomorphine. R-apomorphine is the International Non-Proprietary Name (INN) of the compound (R)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzoquinoline-11,12-diol. Several approaches to develop a system for iontophoretic administration of R-apomorphine have previously been described (see for example R. van der Geest, M. Danhof, H. E. Bodde “lontophoretic Delivery of Apomorphine: In Vitro Optimization and Validation”, Pharm. Res. (1997), 14, 1797-1802; M. Danhof, R. van der Geest, T. van Laar, H. E. Bodde, “An integrated pharmacokinetic-pharmacodynamic approach to optimization of R-apomorphine delivery in Parkinson's disease”, Advanced Drug Delivery Reviews (1998), 33, 253-263). However, in spite of these efforts, only concentrations at the lower end of the therapeutic concentration range of 1.4 to 10.7 ng/ml could be obtained.
A further dopamine antagonist is ropinirole hydrochloride. Ropinirole (INN) is (4-[2-dipropylamina)ethyl]-1,3-dihydro-2H-indol-2-one). Although the iontophoretic administration of ropinirole was considered feasible, it was only possible to obtain fluxes at the lower end of the therapeutic range (see A. Luzardo-Alvarez, M. B. Delgado-Charro, J. Blanco-Mendez, “Iontophoretic Delivery of Ropinirole Hydrochloride: Effect of Current Density and Vehicle Formulation”, Pharmaceutical Research (2001), 18 (12), 1714-1720).
WO2004/050083 relates to a method for treating or alleviating symptoms of Parkinson's disease, which uses iontophoretic delivery of the dopamine receptor agonist rotigotine. The composition used in the iontophoretic delivery system comprises rotigotine in form of its hydrochloride salt and at least one chloride salt in a concentration of 1 to 140 mmol/l the composition having a pH of 4 to 6.5. For an optimal performance a concentration of at least 0.5 mg/ml of the rotigotine hydrochloride is preferred, as derived from Example 1 and 2 of the European patent.
Although, investigating the transdermal iontophoretic delivery of rotigotine.HCl revealed that by applying an electrical current across the skin higher steady state fluxes can be achieved with a shorter lag time compared to passive delivery in these studies the maximum solubility of rotigotine.HCl in the donor phase appeared to be the limiting factor for its iontophoretic transport through the skin. It has been tried to increase the solubility of rotigotine by changing the donor solution, e.g. by adding surfactants or co-solvents or changing the source of Cl− ions. A disadvantage of this iontophoretic delivery system is that e.g. an increase of sodium chloride concentration results in a decrease of the rotigotine flux.
A further limiting factor is the limited solubility of rotigotine hydrochloride in aqueous solvents as well as the strong salting out effect of e.g. sodium chloride.
Many patients need concentrations that are significantly higher than the ones feasible using iontophoretic delivery of the above mentioned compositions and/or are in need for an administration for a longer time period.
There is still a need to develop a transdermal delivery system providing on one hand a greater dosing flexibility (e.g. individual dosing) and on the other hand allowing continuous as well as pulsatile administration, if suitable for an extended period of time.
An object of the present invention is to control (i.e. to canalise/manoeuvre) the transport of rotigotine towards and across the skin from a drug reservoir, thereby optimizing the administration of the individual amount of rotigotine needed by the patient, enhancing the flux of rotigotine across the TDS/skin interface.
Another object and aspect of the present invention is to provide a suitable composition which lead to an enhanced delivery of rotigotine to and across the skin over a period of at least 24 hours, preferably longer than 24 hours.
Another object of the present invention is to provide a continuous as well as pulsatile delivery of the active compound across.